A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study.
Identifieur interne : 000905 ( Main/Corpus ); précédent : 000904; suivant : 000906A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study.
Auteurs : Tien-Tzu Tai ; Tzung-Ju Wu ; Huey-Dong Wu ; Yi-Chen Tsai ; Hui-Ting Wang ; An-Min Wang ; Sheue-Fang Shih ; Yee-Chun ChenSource :
- Clinical and translational science [ 1752-8062 ] ; 2021.
English descriptors
- KwdEn :
- Administration, Inhalation (MeSH), Animals (MeSH), COVID-19 (drug therapy), Female (MeSH), Hydroxychloroquine (administration & dosage), Hydroxychloroquine (adverse effects), Hydroxychloroquine (pharmacokinetics), Liposomes (MeSH), Lung (metabolism), Rats (MeSH), Rats, Sprague-Dawley (MeSH), SARS-CoV-2 (MeSH).
- MESH :
- chemical , administration & dosage : Hydroxychloroquine.
- chemical , adverse effects : Hydroxychloroquine.
- drug therapy : COVID-19.
- metabolism : Lung.
- chemical , pharmacokinetics : Hydroxychloroquine.
- Administration, Inhalation, Animals, Female, Liposomes, Rats, Rats, Sprague-Dawley, SARS-CoV-2.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague-Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30-fold) lung exposure, longer (~ 2.5-fold) half-life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (Cmax ) and 74% of area under the curve from 0 to 72 hours (AUC0-72 ) and lower heart exposure with 23% of Cmax and 58% of AUC0-24 (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.
DOI: 10.1111/cts.12923
PubMed: 33135382
PubMed Central: PMC7877818
Links to Exploration step
pubmed:33135382Le document en format XML
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Therapy, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Tsai, Yi Chen" sort="Tsai, Yi Chen" uniqKey="Tsai Y" first="Yi-Chen" last="Tsai">Yi-Chen Tsai</name><affiliation><nlm:affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Hui Ting" sort="Wang, Hui Ting" uniqKey="Wang H" first="Hui-Ting" last="Wang">Hui-Ting Wang</name><affiliation><nlm:affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, An Min" sort="Wang, An Min" uniqKey="Wang A" first="An-Min" last="Wang">An-Min Wang</name><affiliation><nlm:affiliation>Division of Product Development, Department of Medical Science, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Shih, Sheue Fang" sort="Shih, Sheue Fang" uniqKey="Shih S" first="Sheue-Fang" last="Shih">Sheue-Fang Shih</name><affiliation><nlm:affiliation>Division of Product Development, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Chen, Yee Chun" sort="Chen, Yee Chun" uniqKey="Chen Y" first="Yee-Chun" last="Chen">Yee-Chun Chen</name><affiliation><nlm:affiliation>Division of Infectious disease, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2021">2021</date><idno type="RBID">pubmed:33135382</idno><idno type="pmid">33135382</idno><idno type="doi">10.1111/cts.12923</idno><idno type="pmc">PMC7877818</idno><idno type="wicri:Area/Main/Corpus">000905</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000905</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study.</title><author><name sortKey="Tai, Tien Tzu" sort="Tai, Tien Tzu" uniqKey="Tai T" first="Tien-Tzu" last="Tai">Tien-Tzu Tai</name><affiliation><nlm:affiliation>Division of Corporate Development, Department of Regulatory Affairs, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Wu, Tzung Ju" sort="Wu, Tzung Ju" uniqKey="Wu T" first="Tzung-Ju" last="Wu">Tzung-Ju Wu</name><affiliation><nlm:affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Wu, Huey Dong" sort="Wu, Huey Dong" uniqKey="Wu H" first="Huey-Dong" last="Wu">Huey-Dong Wu</name><affiliation><nlm:affiliation>Division of Respiratory Therapy, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Tsai, Yi Chen" sort="Tsai, Yi Chen" uniqKey="Tsai Y" first="Yi-Chen" last="Tsai">Yi-Chen Tsai</name><affiliation><nlm:affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Hui Ting" sort="Wang, Hui Ting" uniqKey="Wang H" first="Hui-Ting" last="Wang">Hui-Ting Wang</name><affiliation><nlm:affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, An Min" sort="Wang, An Min" uniqKey="Wang A" first="An-Min" last="Wang">An-Min Wang</name><affiliation><nlm:affiliation>Division of Product Development, Department of Medical Science, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Shih, Sheue Fang" sort="Shih, Sheue Fang" uniqKey="Shih S" first="Sheue-Fang" last="Shih">Sheue-Fang Shih</name><affiliation><nlm:affiliation>Division of Product Development, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</nlm:affiliation></affiliation></author><author><name sortKey="Chen, Yee Chun" sort="Chen, Yee Chun" uniqKey="Chen Y" first="Yee-Chun" last="Chen">Yee-Chun Chen</name><affiliation><nlm:affiliation>Division of Infectious disease, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Clinical and translational science</title><idno type="eISSN">1752-8062</idno><imprint><date when="2021" type="published">2021</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Administration, Inhalation (MeSH)</term><term>Animals (MeSH)</term><term>COVID-19 (drug therapy)</term><term>Female (MeSH)</term><term>Hydroxychloroquine (administration & dosage)</term><term>Hydroxychloroquine (adverse effects)</term><term>Hydroxychloroquine (pharmacokinetics)</term><term>Liposomes (MeSH)</term><term>Lung (metabolism)</term><term>Rats (MeSH)</term><term>Rats, Sprague-Dawley (MeSH)</term><term>SARS-CoV-2 (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>COVID-19</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Administration, Inhalation</term><term>Animals</term><term>Female</term><term>Liposomes</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>SARS-CoV-2</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague-Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30-fold) lung exposure, longer (~ 2.5-fold) half-life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (C<sub>max</sub> ) and 74% of area under the curve from 0 to 72 hours (AUC<sub>0-72</sub> ) and lower heart exposure with 23% of C<sub>max</sub> and 58% of AUC<sub>0-24</sub> (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">33135382</PMID><DateCompleted><Year>2021</Year><Month>02</Month><Day>22</Day></DateCompleted><DateRevised><Year>2021</Year><Month>02</Month><Day>22</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1752-8062</ISSN><JournalIssue CitedMedium="Internet"><Volume>14</Volume><Issue>1</Issue><PubDate><Year>2021</Year><Month>01</Month></PubDate></JournalIssue><Title>Clinical and translational science</Title><ISOAbbreviation>Clin Transl Sci</ISOAbbreviation></Journal><ArticleTitle>A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study.</ArticleTitle><Pagination><MedlinePgn>132-136</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1111/cts.12923</ELocationID><Abstract><AbstractText>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague-Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30-fold) lung exposure, longer (~ 2.5-fold) half-life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (C<sub>max</sub> ) and 74% of area under the curve from 0 to 72 hours (AUC<sub>0-72</sub> ) and lower heart exposure with 23% of C<sub>max</sub> and 58% of AUC<sub>0-24</sub> (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.</AbstractText><CopyrightInformation>© 2020 Taiwan Liposome Company, Ltd. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Tai</LastName><ForeName>Tien-Tzu</ForeName><Initials>TT</Initials><AffiliationInfo><Affiliation>Division of Corporate Development, Department of Regulatory Affairs, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Tzung-Ju</ForeName><Initials>TJ</Initials><AffiliationInfo><Affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Huey-Dong</ForeName><Initials>HD</Initials><AffiliationInfo><Affiliation>Division of Respiratory Therapy, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tsai</LastName><ForeName>Yi-Chen</ForeName><Initials>YC</Initials><AffiliationInfo><Affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Hui-Ting</ForeName><Initials>HT</Initials><AffiliationInfo><Affiliation>Division of Product Development, Department of Pharmacokinetics, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>An-Min</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>Division of Product Development, Department of Medical Science, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shih</LastName><ForeName>Sheue-Fang</ForeName><Initials>SF</Initials><AffiliationInfo><Affiliation>Division of Product Development, Taiwan Liposome Company, Ltd., Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Yee-Chun</ForeName><Initials>YC</Initials><AffiliationInfo><Affiliation>Division of Infectious disease, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Agency>Taiwan Liposome Company, Ltd.</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>11</Month><Day>30</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Clin Transl Sci</MedlineTA><NlmUniqueID>101474067</NlmUniqueID><ISSNLinking>1752-8054</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008081">Liposomes</NameOfSubstance></Chemical><Chemical><RegistryNumber>4QWG6N8QKH</RegistryNumber><NameOfSubstance UI="D006886">Hydroxychloroquine</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Protocol" UI="C000705127">COVID-19 drug treatment</SupplMeshName></SupplMeshList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000280" MajorTopicYN="N">Administration, Inhalation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000086382" MajorTopicYN="N">COVID-19</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006886" MajorTopicYN="N">Hydroxychloroquine</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008081" MajorTopicYN="N">Liposomes</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008168" MajorTopicYN="N">Lung</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, 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